Single-cell sequencing-based elucidation of the molecular mechanisms by which the COVID-19 mRNA vaccine remodels the tumor microenvironment and sensitizes immune checkpoint inhibitors via the IFN-I pathway

COVID‑19 mRNA vaccines activate the type I interferon (IFN‑I) pathway and exert anti‑tumor immunomodulatory effects, yet the mechanisms underlying tumor microenvironment (TME) remodeling and immune checkpoint inhibitor (ICI) sensitization remain poorly defined. Public single‑cell, bulk and multi‑omics datasets were integrated with Seurat, CellChat and WGCNA to characterize post‑vaccination IFN‑I activation kinetics, immune‑cell dynamics, and the association between IFN‑I signaling and tumor PD‑L1 expression. An ICI‑response predictive signature was built, and mechanistic conservation was verified using transcriptomic profiles from tumor‑bearing mice. IFN‑I activity peaks at day 3 post‑vaccination and returns to baseline by day 14, accompanied by expanded anti‑tumor immune populations and reduced M2‑like macrophages that mitigate TME immunosuppression. A dual‑regulatory model is proposed: mRNA vaccines drive cold‑to‑hot tumor conversion through IFN‑I‑mediated immune recruitment, while elevating tumor‑intrinsic PD‑L1 to amplify ICI therapeutic potency. The derived signature discriminates ICI clinical responders with favorable performance, and cross‑species analysis confirms conservation of this immunoregulatory cascade. This work elucidates the IFN‑I‑dependent mechanism enabling mRNA‑vaccine‑mediated TME reprogramming for augmented ICI efficacy, offering candidate biomarkers and theoretical support for combinatorial anti‑tumor strategies.